The overall goal of this project is to determine the role of the central nervous system in the cardiovascular effects of cocaine and its metabolites, benzolecogonine and coca ethylene and to investigate their mechanism of action. It is now clear that cocaine alters heart rate dynamics and has cardiotoxic effects. Due to excessive stimulation, cocaine can cause life-threatening problems in multiple organ systems and sudden deaths have been attributed to myocardial ischemia, arrhythmias, strokes and seizures. Cocaine is a new and previously unrecognized risk factor for heart disease. Central dopaminergic mechanisms are important in the behavioral and reinforcing properties of cocaine but the mechanisms of the central cardiovascular actions of systemically administered cocaine are not completely known. Therefore, the behavioral and central cardiovascular effects of cocaine and the metabolites will be compared in conscious chronically instrumented rats using stereotaxic surgical approaches and biotelemetry. The heart rate, blood pressure, core body temperature, motor activities and aversion in the elevated plus-maze are the cardiovascular and behavioral end points to be evaluated following acute and sub acute administration of cocaine and the metabolites. Furthermore, a pharmacogenetic approach will be used to test the hypothesis that genetic factors may play a role in individual sensitivity to cocaine's cardiovascular and behavioral effects using Long Evans Hooded, Lewis and Fischer rats. A final series of experiments will determine the expression of dopamine D1 and D2 receptor subtypes and transporter expression by Northern analysis in the heart and brain structures following cocaine administration. These studies will provide additional knowledge to better understand the mechanisms of the cardiotoxic effects of cocaine and will be valuable in the management of cocaine intoxication.